The fragile X syndrome is the most frequently encountered form of inherited mental retardation in humans and has a prevalence estimated to be 1/1250 males. The fragile X syndrome segregates as an X-linked dominant disorder with reduced penetrance. Either sex when carrying the fragile X mutation may exhibit mental deficiency. It has been shown that approximately 30% of carrier females are penetrant and that 20% of males carrying the fragile X chromosome are normal but may transmit the disorder and have fully penetrant grandsons. In addition to the mental retardation which is variable in severity, penetrant males exhibit additional phenotypic involvement including macroorchidism and distinctive facies. Since fully penetrant males rarely reproduce, it has been suggested that the frequency of new mutations of the fragile X site may be as high as 1/3000 germ cells to maintain the population frequency.
The fragile X syndrome, as implied by its name, is associated with a fragile site expressed as an isochromatid gap in the metaphase chromosome at map position Xq 27.3. The fragile X site is induced by cell culture conditions which perturb deoxypyrimidine pools and is rarely observed in greater than 50% of the metaphase spreads. Neither the molecular nature of the fragile X site, nor its relationship to the gene responsible for the clinical expression of the syndrome is understood. However, based upon genetic linkage studies, as well as in situ hybridizations, the fragile X site and its associated gene are tightly linked if not coincident.
The present application provides a new procedure for detecting the fragile X site at the molecular level. It provides a molecular method for the diagnosis of the fragile X syndrome, describes a unique open reading sequence at the suspected gene locus and provides probes to the fragile X region.